PROJECT SUMMARY Spinal cord injury (SCI) results in the loss of voluntary control of the body part below the injury site. Severed connection between the brain neurons with long-projecting descending axons and the spinal circuits below the lesion is one main cause of such paralysis. Thus, promoting transected axons to regenerate across lesion represents the most ideal strategy for re-building circuits and restoring functions. However, these adult descending axons are regeneration-refractory. Recent studies suggested that a key reason for their regeneration failure is the diminished intrinsic regenerative capacity after injury in adult. In this regard, we and others showed that deletion of PTEN, a negative regulator of mTOR, in either young or adult corticospinal neurons is able to activates their intrinsic regenerative ability, resulting in robust re-growth of transected corticospinal tract (CST) axons. While providing new venues of enabling injured CST axons to mount a regenerative response, these results raise several challenges towards translating these findings to a possible therapeutic strategy. First, while PTEN deletion in cortical neurons resulted in significant CST regrowth, achieving robust and long-distance regeneration for functional recovery might need further optimization of the intrinsic regenerative ability of these mature corticospinal neurons. Second, considering the importance of other descending tracts (in addition to CST), it is important to assess whether their regenerations are also regulated by such manipulations. Third, While PTEN inhibition provides a valuable manipulation for proof-of- principle studies, the biological nature of PTEN as a tumor suppressor raises safety concerns for its clinical application. Thus, it is crucial to develop other safe methods of mimicking the effects of PTEN inhibition in activating mTOR and promoting axon regeneration and functional recovery. The proposed studies in this application will extend our recent exciting findings to address each of these issues, in a hope to develop clinically relevant neural repair strategies for spinal cord injury.